The present disclosure relates to wortmannin analogs and metabolites thereof, and has application to methods of using these derivatives to inhibit phosphotidylinositol-3-kinase (PI-3-kinase) activity and to treat certain malignant tumors.
The PI-3 kinases are a family of related enzymes that are capable of phosphorylating the 3 position hydroxyl group of the inositol ring of phosphatidylinositol. They are linked to a diverse list of cellular functions, including cell growth, proliferation, differentiation, motility, survival and intracellular trafficking. Many of these functions relate to the ability of the PI-3 kinases to activate the protein kinase B (Akt). Genetic and pharmacological inactivation of the p110δ isoform of the PI-3 kinase has revealed this enzyme to be important for the function of T cells, B cell, mast cells and neutrophils. Hence, p110δ is considered to be a promising target for drugs that aim to prevent or treat inflammation and autoimmunity and transplant rejection. Recent evidence has shown that the gene encoding the p110α isoform of the PI-3 kinase is mutated in a range of human cancers. For example, mutation of p110α which leads to over-expression of the kinase is found in human lung cancer. PI-3 kinase activity is also found to be elevated in ovarian, head and neck, urinary tract, colon and cervical cancers. Further, a phosphatase (PtdIns(3,4,5)P3) which antagonizes PI-3 kinase activity is absent or mutated in a variety of human cancers, including advanced prostate, endometrial, renal, glial, melanoma, and small cell lung cancers. Thus, inhibition of PI-3 kinase activity may provide a potential target for treatment of certain human cancers.
Wortmannin is a naturally occurring compound isolated from culture broths of the fungus Penicillium wortmannin that has the basic structure shown in U.S. Pat. No. 5,480,906, which is incorporated herein by reference. Wortmannin irreversibly inhibits PI-3-kinase through covalent interaction with a specific lysine on the kinase: Lys802 of the ATP binding pocket of the catalytic site of the p110α isoform or Lys883 of the p110δ isoform. Most isoforms of PI-3 kinase, such as p110α, p110β, p110δ and p110γ for example, are inhibited equally by wortmannin. Wortmannin demonstrates liver and hematologic toxicity, however, and is a biologically unstable molecule. Samples stored as aqueous solutions at either 37° C. or 0° C. at neutral pH are subject to decomposition by hydrolytic opening of the furan ring. It has been shown that the electrophilicity of the furan ring is central to the inhibitory activity of wortmannin. The irreversible inhibition of PI-3-kinase occurs by formation of an enamine following the attack of the active lysine of the kinase on the furan ring at position C(20) of wortmannin. Thus, decomposition of wortmannin may interfere with its inhibitory activity on PI-3 kinases.
Analogs of wortmannin that display improved biological stability and reduced systemic toxicity may provide improved treatment for cancer and act as anti-tumor agents. Accordingly, what is needed are analogs of wortmannin and metabolites thereof that display increased biological stability and reduced toxicity.